Tumors follow stem cells to bone

A stem cell homing signal may explain why so many cancers spread to bone tissue

By Katherine Bagley | March 28, 2011

Researchers have identified a molecular mechanism that may explain why so many cancers spread to patients' bones -- they piggyback on signaling pathways that hematopoietic stem cells use to home to the bone marrow for self-renewal.

The mechanism, discovered in prostate cancer cells and published online last week in the Journal of Clinical Investigation, may hold implications for a variety of cancers, including breast, lung and colon, which also tend to metastasize to bone tissue, and may have implications for the development of therapies to thwart cancer spread.
"This paper represents an important addition to our understanding of the bone metastatic process," linkurl:David Roodman,;http://www.dept-med.pitt.edu/hemaonc/faculty_info.aspx?fp=4993 director of the Center for Bone Biology at the University of Pittsburg Medical Center who was not involved in the study, said in an email. "The research may provide potential new targets for preventing metastasis."
Nearly 70 percent of patients with breast or prostate cancers, and approximately 15 to 30 percent of those with lung, colon, stomach, bladder, uterus, rectum, thyroid and kidney carcinomas, develop tumors on their bones. Scientists have previously linked this pattern to blood flow, which can carry cancer cells to the bone marrow, and the close proximity of many primary tumors with underlying bones, but many believed anatomy alone couldn't fully explain why these cancers were so much more likely to spread to the bones than other tissues in the body.
Five years ago, researchers discovered how stem cells home to the bone marrow for renewal and dormancy -- a mechanism involving the protein stromal-derived factor-1 (SDF1), and its receptor CXCR4. Upon learning of these findings, bone biologist linkurl:Russell Taichman;http://www.dent.umich.edu/pom/faculty/links/rtbio of the University of Michigan wondered if cancer cells used the same signal. It turns out they do, he told The Scientist.
Taichman and his colleagues implanted human prostate cancer cells into mice and tracked the cells, and found that they target the same niche within bone marrow as human hematopoietic stem cells. The cancer cells appear to directly compete with the stem cells for the limited space in the niche, where they become dormant until unknown factors later trigger new tumor growth.
The researchers then tested the effects of AMD3100, a compound commonly used to antagonize SDF1, forcing stem cells to leave the bone and enter the blood stream. Sure enough, the team found that AMD3100 does the same to prostate cancer cells -- ejecting them from the bone and dumping them into circulation -- suggesting that like stem cells, prostate tumors use SDF1 to home to the bone marrow.
The scientists also observed that mice with prostate cancer have lower expression levels of niche adhesion molecules and transcription factors known to regulate stem cell self-renewal and proliferation in bone marrow. The finding indicates the cancer cells may be able to reduce stem cell numbers in bone marrow by altering their proliferation patterns, providing more niche space for themselves, Taichman said.
The results could hold implications for treating cancers that spread to bone, wrote Laura G. Schuettpelz, a pediatrician in St. Louis, Missouri, and Daniel C. Link, a researcher at Washington University in St. Louis, in an accompanying commentary. Because cancer cells are resistant to chemotherapy when they lie dormant in bone marrow, using activating agents, such as AMD3100, to force cancer cells into the blood stream may make them susceptible to the treatment, wrote Schuettpelz and Link. This could help prevent recurrent tumors that appear in bones after the primary tumors have been eradicated by chemotherapy.
"These are carefully done, technically challenging studies using a variety of innovative approaches to address an important and relevant clinical problem," said Roodman.
Correction: This article has been updated from its original version to correctly list the authors of the accompanying commentary in the Journal of Clinical Investigation as Laura G. Schuettpelz and Daniel C. Link. The Scientist regrets the error.Y. Shiozawa, et al., "Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow," linkurl:J Clin Invest,;http://www.jci.org/articles/view/43414/pdf doi:10.1172/JCI43414, 2011.**__Related stories:__*** linkurl:New metastasis marker found;http://www.the-scientist.com/news/display/57970/ [1st February 2011]*linkurl:New metastasis mechanism revealed;http://www.the-scientist.com/blog/display/54521/ [3rd April 2008]*linkurl:Cancer stem cells drive metastasis;http://www.the-scientist.com/news/display/53583/ [12th September 2007]

Comments

Editors,\n\n\nI find the paper really interesting, and fascinating. However, I must emphasise an overlooked aspect in using stem cells in humans, I have illustrated in a lot of former comments, even on The Scientist website (http://www.the-scientist.com/news/display/53836/.\nI have written at URL\nhttp://www.washingtonpost.com/ac2/wpdyn/comments/display?contentID=AR2007041101736&start=41, that there is a fundamental bias in present utilisation of stem cells. In my opinion, a great lot of money on studying staminal cells, even in amnyotic fluid, accounts for the reason there is an overlooked bias in such as research articles! In fact, in performing staminal cell researches all around the world scientists overlook both an inherited mithocondrial cytopathy, I termed Congenital Acidosic Enzyme-Metabolic Histangiopathy and Biophysical-Semeiotic Constitutions 1-6 See website For instance: accordingly, type 2 diabetes is a major problem worldwide, a real epidaemic. Independent of different countries, in recent decades diabetes prevalence has increased rapidly over time among both developed and developing populations. Surely, genetic factors alone cannot explain these patterns. However, as allows me to state my clinical experience, See URL: an individual, without diabetic AND dyslipidemic biophysical-semeiotic constitutions, can not be involved by type 2 diabets, at all 1-6. Certainly, rapid changes in lifestyle and risk factors such as obesity, unhealthy diets, physical inactivity, tobacco smoking, a.s.o., acting on people with diabetic and dyslipidaemic constitution may cause, AT FIRST, Pre-Metabolic Syndrome, then, over years or decades, metabolic syndrome 2, 6, IGT, and finally type 2 diabetes. In a few words, all around the world, e.g., the war against diabetes mellitus and its well-known and harmful complications, as well as the war against all other serious and common human diseases, is nowadays possible, also utilizing possibly stem cells of whatever origin, exclusively by means of a primary prevention, which must be perform at the bed-side, i.e., clinically, on a very large scale, using the simple stethoscope. In addition, we must in the future utilize stem cell, even of amnyotic fluid, of individuals not involved by above-cited biophysical semeiotic constitutions! In other words, in both primary prevention and screening programme for whatever disease, including DM and its complications, and cancer, we need efficacious clinical tools to obtain the best results, avoiding, e.g., to use stem cell with impaired mitochondria. Really, early diagnosis must certainly be established in asymptomatic patients, who, for example, are evolving slowly towards diabetes mellitus, i.e. long time before disease onset, in order to avoid the well known, severe complications. In fact, to prevent these diabetic complications, including diabetic retinopathy, on very large scale it is extremely necessary that doctors use a clinical tool reliable in diagnosing early diabetes mellitus stages, from initial stages, i.e., biophysical-semeiotic constitutions, and then the Pre-Metabolic Syndrome See my website, useful particularly in selecting appropriate stem cells to be utilized. As I wrote formerly in PLOS, physicians can fortunately utilize bedside clinical methods reliable in ascertain the truth of articles published in famous peer reviews. \nReferences \n1 Stagnaro S., Stagnaro-Neri M. Valutazione percusso-ascoltatoria del Diabete Mellito. Aspetti teorici e pratici. Epat. 32, 131 1986 \n2 Stagnaro Sergio, Stagnaro-Neri Marina. Introduzione alla Semeiotica Biofisica. Il Terreno oncologico. Travel Factory SRL., Roma, 2004 \n3 Stagnaro S., Stagnaro-Neri M., Le Costituzioni Semeiotico-Biofisiche.Strumento clinico fondamentale per la prevenzione primaria e la definizione della Single Patient Based Medicine. Ediz. Travel Factory, Roma, 2004. \n4 Stagnaro S., Istangiopatia Congenita Acidosica Enzimo-Metabolica. Una Patologia Mitocondriale Ignorata. Gazz Med. It. - Arch. Sci. Med. 144, 423,1985 Infotrieve.\n 5 Stagnaro S. Diet and Risk of Type 2 Diabetes. N Engl J Med. 2002 Jan 243464:297-298. [MEDLINE]. \n6 Stagnaro S.-Neri M..Stagnaro S., Sindrome di Reaven, classica e variante, in evoluzione diabetica. Il ruolo della Carnitina nella prevenzione del diabetemellito. Il Cuore. 6, 617, 1993, [MEDLINE].\nBy dottsergio | Apr 12, 2007 12:31:12 PM |\n\n

i suspect apart from carcinogens,intoxicated cells tends to multiply and become cancerous,\nexample , mouth intoxicated by tobacco, lungs by cigarettes, cervix by copulation,breast by breast feeding and copulation,intestine by masala orflavoured foods, utreus by coupulation or by zycote,and then spread to other parts.maligned cancer,benign becomes maligned,when spread to other parts.\n\nHumans tend to multiply, when they are contended and happy,similarly body cells.Cells and human are not different.